A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage

Christiansen, Ole Bjarne; Pedersen, Bjørn Panyella; Rosgaard, Anni; Husth, Merete

doi:10.1093/humrep/17.3.809

Cited by 142 publications

(144 citation statements)

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“…In another study, the prevalence of a 14 base pair insertion in exon 8 of the HLA-G gene was found to be increased significantly in secondary RM patients, compared with controls. These studies provide evidence that particular HLA polymorphisms characterize secondary RM [5][6][7].Huge heterogeneity between eight randomized placebocontrolled trials of IVIg to patients with RM has been observed, with live birth rates in placebo groups ranging from 29 to 79% [8][9][10][11][12][13][14][15]. The differences in live birth rates observed between these studies raises questions as to whether the patient categories are the same.…”

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confidence: 99%

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Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics

Christiansen

2014

Clin Exp Immunol

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Recurrent miscarriage (RM) is the occurrence of three or more consecutive miscarriages before gestational week 20 and is a condition that affects 1-3% of women [1]. RM can be classified into two categories: primary RM (no prior live birth) or secondary RM (three or more consecutive miscarriages following a live birth). In addition to genetic and anatomical factors causing RM, many studies have suggested that signs of autoimmunity and dysregulation of natural killer (NK) cell immunity characterize women with RM.Approximately 25 years ago, the first pilot studies on the use of intravenous immunoglobulin (IVIg) for the treatment of RM were conducted and reported a live birth rate of 80-82% [2,3], which provided support to warrant further investigation in placebo-controlled trials. In 2006, a Cochrane review of IVIg treatment for RM in eight placebo-controlled trials with 303 RM patients was conducted, concluding that IVIg did not increase live birth rates when compared to placebo [odds ratio (OR) = 0·98; 95% confidence interval (CI) = 0·61-1·58] [4]. However, this review did not differentiate between primary and secondary RM patients. Separate analysis of these two subsets of RM patients may be necessary, as several studies have observed that secondary RM is a condition dominated by immunological risk factors when compared to primary RM, suggesting large heterogeneity between these two subgroups.Tumour necrosis factor (TNF)-α is a cytokine involved in the immune system's inflammatory response. Piosik et al. analysed peripheral blood samples of RM patients taken at gestational week 5, and found that TNF-α levels were increased significantly in secondary RM patients compared to primary RM patients (P = 0·042) [1]. This indicates that secondary RM is a condition with an increased proinflammatory response in early pregnancy.More evidence of the role of immunological factors in secondary RM has been reported in studies that have shown associations between secondary RM patients with specific maternal human leucocyte antigen (HLA) polymorphisms. Kruse et al. found that there was a significantly higher prevalence of the HLA-DRB1*03 allele in secondary RM patients compared with controls (OR = 1·8; 95% CI = 1·3-2·5) [5], whereas the allele was not increased in patients with primary RM. A previous pregnancy with a boy can be a risk factor for secondary RM. In general, maternal immune recognition of male-specific minor histocompatibility (HY) antigens expressed in male fetal and trophoblast cells is well tolerated, resulting in a live birth. However, pregnancy with a boy may prime the mother's HY immunity. Nielsen et al. found that maternal carriage of HLA class II alleles that restrict anti-HY antigen responses reduces the chances of a live birth in secondary RM patients with a firstborn boy compared with a firstborn girl (OR = 0·17; 95% CI = 0·1-0·4; P = 0·0001) [6]. In another study, the prevalence of a 14 base pair insertion in exon 8 of the HLA-G gene was found to be increased significantly in secondary RM patients, compa...

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confidence: 99%

“…Huge heterogeneity between eight randomized placebocontrolled trials of IVIg to patients with RM has been observed, with live birth rates in placebo groups ranging from 29 to 79% [8][9][10][11][12][13][14][15]. The differences in live birth rates observed between these studies raises questions as to whether the patient categories are the same.…”

mentioning

confidence: 99%

Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics

Christiansen

2014

Clin Exp Immunol

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“…There were some observations to support the theory that immunological factors played a greater role in women with a series of miscarriages after a birth (secondary RM) than in women with RM who had never had a successful pregnancy (primary RM). The HLA-DR3 allele found to be associated with RM displayed a much stronger association to secondary than to primary RM [56], and some evidence from immunotherapy studies suggested that a possible therapeutic effect of intravenous immunoglobulin (IvIg) seemed to be restricted to women with secondary RM [57]. During pregnancy fetal cells entered the maternal circulation of the women with secondary RM [58] and in late pregnancy apoptotic syncytiotrophoblast debris is normally shed in large quantities (several grams per day) from the placenta [59].…”

Section: Discussionmentioning

confidence: 99%

“…SRM was hence preceded by a possible priming of the immune system of the mothers that may theoretically lead to harmful immunological reactions against the semi-allogeneic fetus. Many women with secondary RM had developed a harmful immunological reaction against male-specific antigens(HY-antigens) on the trophoblast, and that this results in a subsequent increased miscarriage rate of male conceptions [57]. HY-derived peptides may be presented to maternal immune cells by HLA-G molecules on the trophoblast [60].…”

Section: Discussionmentioning

confidence: 99%

Relationship between HLA-G polymorphism and susceptibility to recurrent miscarriage: A meta-analysis of non-family-based studies

Fan

Huang

et al. 2013

J Assist Reprod Genet

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Purpose The HLA-G 14-bp insertion/deletion polymorphism had been inconsistently associated with recurrent miscarriage (RM) risk. We examined the association by performing a meta-analysis. Methods Eligible articles were searched in PubMed, EMBASE and CNKI without language limitation. We included all the articles about two or more miscarriages associated with HLA-G 14-bp polymorphism. The odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of associations. Statistical analyses were performed by the STATA10.0 software. Results 17 studies were included, representing 1786 cases and 1574 controls. The current meta-analysis showed that 14-bp polymorphism was not associated with RM risk in all genetic models and allele contrast(+14 bp vs. −14 bp: OR=1.13; 95 % CI, 0.96,1.32; +14 bp/+14 bp vs. −14 bp/−14 bp: OR=1.16, 95 % CI, 0.85, 1.59; +14 bp/−14 bp vs. −14 bp/−14 bp: OR= 1.21, 95 % CI, 0.92,1.58; dominant model: OR=1.33; 95 % CI, 0.99,1.78; recessive model: OR = 1.06; 95 % CI, 0.79,1.43). Moreover, a significant heterogeneity was evident across studies. On the other hand, the subgroup analysis demonstrated that there was a significant association between HLA-G 14-bp polymorphism and patients with three or more miscarriages(+14 bp vs. −14 bp: OR=1.27; 95 % CI, 1.04, 1.55; dominant model: OR=1.52; 95 % CI, 1.16, 1.99; and model +14 bp/−14 bp versus −14 bp/−14 bp: OR=1.51; 95 % CI, 1.15, 1.97;). Conclusions Our comprehensive meta-analysis indicated that there was insufficient evidence to demonstrate a conclusive association between the HLA-G 14-bp insertion/deletion polymorphism and the risk of RM. But HLA-G 14-bp insertion/ deletion polymorphic variation was associated with RM risk in patients with three or more miscarriages. Larger and welldesigned studies may eventually provide a better, comprehensive understanding of the association between the HLA-G 14-bp insertion/deletion polymorphism and RM in the future.

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“…Paternal mononuclear cell immunization has been proved not to be effective (Scott, 2003). It is believed that passive immunotherapy with intravenous immunoglobulin (IVIG) may offer benefit in idiopathic secondary (at least one prior ongoing pregnancy), but not idiopathic primary (no prior ongoing pregnancy) recurrent miscarriage (Christiansen et al, 2002). However, such conclusions must be taken with caution because of small heterogeneous sample size.…”

Section: Immunotherapymentioning

confidence: 99%

The Role of Glucocorticoids in Pregnancy: Four Decades Experience with Use of Betamethasone in the Prevention of Pregnancy Loss

Vesce¹,

Giugliano²,

Cagnazzo³

et al. 2012

Glucocorticoids - New Recognition of Our Familiar Friend

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A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage

Abstract: IvIg may improve pregnancy outcome in patients with secondary RM. A new placebo-controlled trial focusing on this subgroup should be conducted to confirm the results.

Cited by 142 publications

References 22 publications

Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics

Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics

Relationship between HLA-G polymorphism and susceptibility to recurrent miscarriage: A meta-analysis of non-family-based studies

The Role of Glucocorticoids in Pregnancy: Four Decades Experience with Use of Betamethasone in the Prevention of Pregnancy Loss

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